Stem cells, defined by their unlimited or prolonged capacity for self-renewal, are essential for the development and homeostasis of multicellular organisms. Their decision between self-renewal and differentiation is governed by both cell-autonomous (intrinsic) signals and extrinsic stimuli from the surrounding microenvironment, or "niche." While stem cells hold promise for regenerative therapies, their dysregulation can lead to cancer. A thorough understanding of both stem cells and their environmental control is, therefore, critical for the effective treatment of cancer and development of stem cell therapies. The long-term objective of this research proposal is to identify the cellular and molecular mechanisms used by a niche to regulate stem cells, using the well-defined C. elegans gonad as a model. To achieve this goal, germline stem cells will first be better characterized using criteria employed widely for other types of stem cells (cell cycle length and self-renewal capacity). Niche mechanisms for regulating germline stem cells will then be elucidated using a cell-specific whole-genome RNAi approach to identify all genes required in the niche for maintenance of germline stem cells.